Review
Disorders of Transepidermal Elimination Part 1
THOMASY. Woo, M.D., AND JAMES E. RASMUSSEN, M.D.
Transepidermal elimination (TE) is a mechanism From the Department of Dermatology, Division of whereby foreign or altered constituents can be re- Medicine, University of Calgary Faculty of Medicine, moved from the dermis. This process involves unique Calgary, Alberta, Canada and the Department of Dermatology, University of Michigan Medical School, morphologic alterations of the epidermis, which forms Ann Arbor, Michigan a channel and thereby facilitates extrusion of the desired dermal components. The phenomenon of TE may occur as a primary process characterizing dis- spaces and hence be carried upward. From the point orders, such as elastosis perforans serpiginosa and of view of the dermis and epidermis, types 1 and 2 reactive perforating collagenosis. Occasionally, TE are relatively passive processes and have been termed may occur as a secondary phenomenon. Well-known "transmigration." This phenomenon is relatively examples are perforating granuloma annulare and common and is often an incidental finding. Once on pseudoxanthoma elasticum. the surface, the material is desquamated along with the adjacent corneocytes. Disorders of Transepidermal Elimination Type 3, however, involves active epithelial-dermal connective tissue interaction and is a purposeful, The human skin is a complex organ in which the directional mechanism whereby dermal foreign com- dermal and epidermal units function together in ponents are actively eliminated through the epithe- complex cellular interactions in response to various lium. This process was observed by Freudenthal,' stimuli. Specifically, many foreign or altered biologic who observed small particles of amyloid being ex- materials present in the dermis will incite such a pelled through the epidermis in 1930. Mehregan series of events aimed at eventual dissolution, isola- formulated this phenomenon, termed it "transepi- tion, or removal of these objects via the epidermis. dermal elimination" (TE), and supported the concept Dermal "foreign material" may be the consequence with an excellent series of observations of various of inflammation, metabolic alterations, neoplastic cells, pathologic en ti tie^.^ He succinctly defined this process or external substances. as There are several mechanisms whereby dermal characterized by varying degrees of pseudoepithelio- foreign material can be transported to the surface of matous hyperplasia of the epidermis or follicular epithe- the skin. Mehregan,' a pioneer in this field, differen- lium. Elongated tongues of newly formed epithelium tiated three basic categories. In type 1, nonmotile extend into the corium surrounding the irritating material. cells such as erythrocytes or small inert particles (eg, Once the material is partially or completely taken into the proliferating epithelium, it is slowly moved upward hemosiderin) elicit minimal or no dermal reaction. by the force of maturing keratinocytes and eventually These particles can be trapped between epithelial eliminated. A continuous tlow and elimination of foreign cells and carried upward to the surface during epi- material to the surface will result in formation of multiple dermal turnover. In type 2, larger cells, such as motile transepithelial perforating canals. cells (eg, leukocytes) or organisms such as Jreponernd The fact that a material was initially present in the pallidurn may actively migrate into the epidermal dermis and subsequently arrives at the epidermal surface does not necessarily imply TE. For instance, foreign bodies or altered dermal components, which This is the first in a series of two articles. Address for correspondence: Thomas Y. woo, M.D., suite 401, elicit a strong inflammatory reaction that ultimately 2681 36th Street, NE, Calgary, Alberta, TlY 553 Canada. leads to epithelial necrosis with purulent draining
267 2 68 INTERNATIONAL JOURNAL OF DERMATOLOGY June 1985 Vol. 24
TABLE1. Disorders of 7ransepidermal Elimination Diseases that primarily exhibit the phenomenon of TE are distinct nosologic entities with characteristic Disorders in which TE is a constant feature clinical morphology, usually an umbilicated papule Elastosis perforans serpiginosa Penicillamine with a central core or plug and a unique histologic Osteogenesis imperfccta presentation. Within the framework of this and a Marfan's syndrome subsequent article, the formulation of this eliminating Ehlers-Danlos syndrome mechanism is highlighted and its characteristic dis- Acrogeria orders emphasized. Most cogently, elastosis perforans Down's syndrome Cutaneous sclerosis serpiginosa (EPS) and reactive perforating collagenosis Reactive perforating collagenosis (RPC) are elaborated in detail, since these are primary Collagenome perforant verruciforme disorders of TE. In addition, we elaborate on other Chondrodermatitis nodularis helicis chronlca entities that secondarily express the phenomenon of Disorders in which TE may occur as a secondary event TE, including perforating granuloma annulare; pseu- Granulomatous disorders Granuloma annulare doxanthoma elasticum; melanoma; nevocellular ne- Necrobiosis Iipoidica iiiabeticoruin vus; calcinosis and osteoma cutis; nevus sebaceous; Rheumatoid nodule infectious agents, such as botryomycosis, chromo- Sarcoid mycosis, and schistosomiasis; necrobiosis lipoidica; Dermatoses with calcification chondrodermatitis nodularis helicis; papular muci- Pseudoxanthoma elasticum Calcified tumor of hair follicle origin nosis; cutaneous sclerosis; lichen nitidus; and rheu- Calcinosis cutis matoid nodule (Table 1). Osteoma cutis Infectious agents Elastosis Perforans Serpiginosa Botryomycosis Schistosomiasis History Chromomycosis Other EPS was initially described by Fisher' in 1927 in a Lichen nitidus patient with a circinate papular eruption on the neck. Papular rnucinosis Histopathologic examination revealed a bluish-staining Melanoma Nevocellular nevus amorphous plug perforating through the epidermis. Porokeratosis of Mibelli At that time, it was thought to be an atypical case of Kyrle's disease. Later, Lutz,' in 1953, presented a 21- year-old man with irregularly shaped keratotic ridges material through a sinus, does not represent TE. The composed of closely set nodules present on both sine qua non of this mechanism resides in the fact sides of the neck. He assumed the lesions to be of that the epithelium does not suffer major structural hair follicle origin and termed them "keratosis follicu- alterations and returns to normal when the process lark serpiginosa." of elimination is terminated through depletion and In 1955, Miescher presented a classical description exhaustion of the material being eliminated. of EPS located on the neck of a 10-year-old boy.8 The signal that induces these reactive changes in The eruption consisted of closely set keratotic papules epidermal architecture is unknown. Both infectious each with a central plug arranged into hyperkeratotic and noninfectious granulomas, exogenous foreign ridges. Individual papules appeared to involute within bodies, and altered dermal components have been 5 months, but the basic process continued unabated implicated as the inciting event.4 Regardless of the forming new lesions. Histologic evaluation revealed type of material, close proximity to the epithelium is acanthosis, hyperkeratosis, and enlargement of the extremely important; for example, subcutaneous epidermal rete ridges, with interruption of the epi- granulomas and deep foreign bodies usually do not dermis by a keratotic plug extending from the epi- induce epithelial hyperpla~ia.~This has been dem- dermis into the dermis. The plugs consisted of elastic ~TSC~~IW' iir tfXpwiirmn\- r+iidsarm' Sdieilknatr, rliiers r.har' were tiiitoibgiiailt well-preserved lower who injected carageenan into different levels of the in the plug, but the higher asc.ending fibers appeared dermis.' Material placed below the level of the hair to lose their staining properties. A homogeneous papillae did not induce hyperplasia. In contrast, mass of elastic fibers (elastoma) was present in adja- placement above this zone resulted in epidermal cent dermal papillae; these papillae were surroundcd proliferation. Thus it appears that in TE elimination, by epidermal rete ridges that protruded downward, the target substance must reside within a certain giving the appearance of the epidermis trying to dermal-epidermal interaction zone. envelope and eliminate the elastic- tibers. Miescher No. 5 TRANSEPIDERMAL ELIMINATION . Woo and Katmutsen 269 interpreted the process to be secondary to poor nutrifion, resulting in "necrobiosis" and expulsion of the altered elastic tissue. He coined the term "elas- torna intrapapillare perforans verruciforme" to de- scribe this process.' In the same year, Beening and Ruiter' reported a similar case in a 13-year-old boy with Down's syn- drome. They considered this to be identical to the condition described earlier by Lutz' and termed it "hyperkeratosis folliculnris serpiginosa." This was probably the first reported case of EPS appearing in conjunction with a genetic disorder. There are a number of entities with which EPS has been asso- ciat d. Uxnmcvt and Putkonrn'" were the first to propose thr n Histology FIG 2 Histopathology of EPS The epidermal channel can be EPS has a characteristic appearance when stained seen as a spiral in longitudinal section Within the channel are with hernatoxylin and eosin or stains for elastic fibers altered eosinophilic elastic fibers (H & E, X100) 2 70 INTERNATIONAL IOURNAL OF DERMATOLOGY June 1985 Vol. 24 of keratinous debris and bluish amorphous crust. The that the amount of elastic tissue in one patient was peripheral portion contains keratinous material, and elevated to 3.5 times that of the control, whereas a central portion of dense bluish-staining "necro- the amount of collagen was only minimally elevated biotic" material consists in part of degenerated epi- in lesional skin.13 thelial cells and pyknotic nuclei of inflammatory cells. In some respects, the lesional skin of EPS resembles Also present within the central area are many brightly that of the newborn or embryonic cutaneous epithe- staining eosinophilic fibers. The fibrous material oc- lium due to several observations. Overall, lesional cupies a tortuous channel and in cross section may elastic tissue appears similar to newly formed elastic occupy small, round, cystic spaces within the epi- fibers. The majority of collagen fibers in EPS are of dermis that appear to lie above one another, giving small diameter and thereby resemble embryonic skin, the appearance of a spiral seen in longitudinal sec- while EPS lesions contain a similar amount of dermal tion.'* These spirals are not epidermal appendages: hydroxylation to the newborn epidermi~.'~ there are no connections with hair follicles or sweat ducts seen on serial section. Association with Other Disorders The epidermis immediately surrounding the per- forating canal is composed of flattened keratinocytes EPS occurs in association with a number of con- that appear to desquamate into the central plug. The nective tissue disorders and a wide variety of other nearby epidermis is acanthotic and produces small diseases. In fact, as many as one quarter of all cases protruberances of epithelium into the upper dermis. of EPS may occur in association with other an~malies.~ These tongues of epidermis appear pseudoepithe- Penicillamine-induced EPS. There are at least liomatous and nonpallisading and are without a well- nine reported of EPS following the admin- organized basement membrane. istration of therapeutic doses of penicillamine, 1.5- The underlying dermis contains occasional foreign 2.0 g daily for up to 6 year^.*^,'^ In 1972, Guilaine et body granulomas of mononuclear phagocytes and aI.l4 described the first case of EPS following penicil- multinucleated giant cells. When perilesional sections lamine treatment for Wilson's disease (hepatolen- are stained for elastic fibers, there is a marked increase ticular degeneration). Subsequently, seven additional in the amount and thickness of fibers. Perilesional cases occuring in similar situations have been re- elastic fibers are seen extending vertically upward ported.15-19 The remaining patient developed EPS into dermal papillae and may lie adjacent to basal following penicillamine treatment for cystinuria (con- cells. in intervening areas between perforating canals, genital defect of homocystine synthetase).*' the superficial plexus of elastic fibers is relatively Clinically, penicillamine-induced EPS appears sim- well-organized and appears normal. As one nears the ilar to primary idiopathic EPS with annular or circinate, perforating canals, a stream of connective tissue keratotic, umbilicated papules on the lower face, containing many altered elastic fibers is seen to enter sides of neck, axillae, and antecubital fossae; however, the canals. The perforating elastic fibers extend to one patient had a discoid, firm-bordered penile lesion the surface of the lesion, where they can be seen with a central depressed area within the inner margin adjacent to the parakeratotic stratum corneum. These of the hyperkeratotic ring." fibers lose their characteristic staining properties and Penicillamine-induced EPS can be differentiated appear brightly eosinophilic using the acid orcein- from the idiopathic type by electron-microscopic Giemsa stain or yellow by the aldehyde fuchsin and, at times, light-microscopic examination. Three method. In contrast to elastic tissue, the amount of morphologically distinct forms of elastic fibers in acid mucopolysaccharide in lesions of EPS is normal. penicillamine-induced EPS may be discerned. First, Ultrastructural abnormalities of the epidermis are there are lateral ("lumpy-bumpy") perpendicular restricted to the site where TE has 0~curred.l~Elec- buddings from elastic fibers present in the deep tron-microscopic examination of the dermis, on the dermis, having the same diameter as the elastic other hand, shows elastic fibers organized into large fiber.'4*'6*'7Second, Kirsch and Hukill17 found intense strands or as an infiltrating substance interspersed eosinophilia of the elastic fibers that were penetrating between collagen bundles. Ill-defined structures are the epidermis, while those in the reticular dermis seen to run parallel to the axis of the elastic fiber, were less eosinophilic or appeared even basophilic. indicating a possible lack of homogenous organization. Third, elastic fibers lack the peripheral fibrils and the This is in conjunction with a filamentous material that alternating bands of dense and light layers normally appears to be newly assembled elastic fibers. The seen within the cortex. elastic fibers in turn are surrounded by tubular- Hashimoto and others have found the collagen appearing microfibrils. Amino acid analysis revealed fibers to be abnormal in several cases of penicillamine- No. 5 TRANSEPIDERMAL ELIMINATION . Woo and Rasmussen 271 induced EPS.’n~2’ 25 F-ibrils were irregular in diameter 4-year-old boy who had a rupture of an anterior and up to five times larger in diameter than normal cerebral artery berry aneurysm but was otherwise fibrils, while transverse sections showed the outer normal. Eide4’ described EPS in association with fatal, limits of the fibrils to be rather ragged. These collagen widespread arterial rupture of the aorta, with dissec- abnormalities resemble those found in Ehlers-Danlos tion and elastosis of the endocardium and bronchiolar syndrome type I and disseminated connective tissue walls in a 30-year-old woman who was otherwise nevi. On this basis, it appears that there is sufficient normal. Anning33 described a similar case in an 18- difference in the composition and morphology of year-old man with a dissecting aneurysm and EPS. It elastic- and collagen fibers to allow differentiation is conceivable that Christianson’s case and the others btxtween idiophathic or penicillamine-induced EPS. occurred in individuals with an undiagnosed mild or Bardach et at.‘“ described a patient who had not incomplete form of Ehlers-Danlos type IV, since only drug-induced EPS but also a large pulmonary air these individuals are prone to arterial rupture and cyst. Idrntical light- and electron-microscopic changes hemorrhage. in both c‘utmeous and adjacent pulmonary elastic Acrogeria. In 1980, Groot et reviewed the tiswe suggrsttd to the authors that the penicillamine literature on acrogeria and found that 4 patients (all had induc cd ‘1 disseminated ”cutaneo-visceral elas- women) of a total of 19 (21%) also had EPS. These tosis.” patients had typical lesions of EPS in both axillae, The pithogenesis of penicillamine-induced EPS in arms, neck, and thighs. Further, two patients had Wilson’s disease is unknown, but it is tempting to high, arched palates. Superficially, acrogeria may be suggc’st an etiologic-role for penicillamine in producing similar to Ehlers-Danlos type IV, with conspicuous relative local cutaneous deficits in copper and thereby cutaneous blood vessels and easy bruising, but it is interfering with normal copper metabolism in the different in that there are neither gross ecchymoses skin.2” More plausible is the theory of Siega126 that nor intestinal hemorrhage in the former. penicillamine inhibits lysine-derived polyfunctional, Down’s Syndrome. Beening and R~iter,~in 1955, intramolecular, cross-linking formation during elastin described the first cases of EPS in association with synthesis. Higher doses may also inhibit lysyl oxidase. Down’s syndrome. Thus far there have been at least These changes could conceivably underlie faulty 15 patients described in the literat~re.’,~,~~-~~Lesions elastin formation with lumpy-bumpy fibers bulging in of EPS in most cases have a similar morphology and all directions beyond the confines of the elastic fiber. appear to occur in similar sites to the idiopathic Osteogenesis Irnperfecta. Osteogenesis imper- variety; however, one of us (J.E.R.) has described the fecta (01) involves connective tissue components occurrence of atypical EPS in four Down’s patients, with manifestations that include pathologic fractures three boys and one Lesions initially appeared and characteristic blue sclera. There are at least seven as classical bilateral, hyperkeratotic papules on the cases of EPS reported to occur in patients with 01. neck and upper extremities. Several years later the Lesions of EPS may occur in localized typical sites, circinate papules were replaced with linear and reti- appearing on the neck in five patients*’-’’ and the form hypopigmented scars, several of which con- antecubital fossa in t~o.~’,~’Disseminated lesions tained a hyperkeratotic papule at one end. isolated have been reported. King~ley~~described the occur- single papules were also seen. Biopsy of a lesion at rence of “extensive and symmetrical” EPS in a 19- one end of a scar was consistent with EPS.45 year-old man with osteogenesis imperfecta. On ex- Whyte and Winkelmann4’ found the incidence of amination, histologic and clinical appearances are EPS in Down’s to be 0 among 287 institutionalized identical to those of the idiopathic variety. patients, although our study revealed an incidence Marfan‘s Syndrome. There have been reports of approximately 10/0?5 The chronicity of EPS in of EPS associated with two individuals having Marfan’s Down’s can be exemplified by a 21-year follow-up ~yndrome,~’and one with a high, arched palate who of a patient who was refractory to innumerable was otherwise treatments, including both topical and oral agents.43 Ehlers-Danlos Syndrome. In 1958, Meara” de- New lesions were still developing while old ones scribed a patient with Ehlers-Danlos syndrome with resolved, leaving hyperpigmented scars. This patient EPS in the antecubital fossa. Since the initial descrip- had an episode of scabies; interestingly, all mites tion, four similar cases have been recovered were within the skin lesions of EPS. L~ndon’~presented a case of a 17-year-old man with Crotty et al.44 studied the biopsy specimens of EPS EPS in conjunction with Ehlers-Danlos type IV (Sack- from the lesional skin on the thigh of a Down’s Barabas arterial ecchymotic type). Another case of patient compared with nonaffected buttock skin. EPS has been described by Christianson3’ in a Although there were no differences on light-micro- 272 INTERNATIONAL IOURNAL OF DERMATOLOGY lune 1985 Vol. 24 scopic examination, electron-microscopic examination It was theorized that symmetry of lesions of EPS revealed the presence of abnormally tine fibrils (14.5 would possibly indicate a genetic or acquired defect nm) in association with the collagen and elastin. They in utero, with the expression of pathology being prior also saw globular formations (2,500 nm diameter) to the 18th day of ge~tation.~’Woerdeman” reported composed of fibrillar material (14.5 nm diameter) the first familial occurrence of EPS in a girl and her occurring in sites subjacent to the basal lamina. In two brothers. A leukocyte chromosomal evaluation contrast, nonaffected skin did not show these abnor- performed on the girl had normal results. Her parents malities. It theretore appears that EPS in Down’s and two other brothers were normal. syndrome may differ in its natural evolution, duration, Recently, Ayala and Donofrio” reported two and ultrastructural appearance from the idiopathic brothers with classic idiopathic EPS on clinical and type. histologic examination. There was no tamily history Cutaneous Sclerosis. Barr et al.48 recently de- of any heritable disorders of connective tissue disease. scribed the first report of EPS in association with Seventeen of 36 total family members were examined, morphea. A 16-year-old woman with morphea pre- and no associated diseases nor other cases of EPS sented with arcuate keratotic papules in the antecu- were found. They postulated that since there have bital fossae that were found on histologic examination been no examples of vertical transmission of EPS to be typical of EPS. In 1981, a report was published reported and since there are now two families in of EPS in association with systemic scler~derma.~~whom EPS has occurred in the siblings, the mode of Both patients had never been treated with penicilla- inheritance may be autosomal recessive. mine. It has been postulated48 that these represent examples of perforating morphea-scleroderma on Diagnosis the basis of the abnormal elastic fibers in the perfo- Identification is based on the characteristic clinical ration in continuity with abnormal elastic fibers within appearance with verrucous papules containing a cen- the sclerotic foci. At this time it would seem prudent tral plug and histologic presentation of perforating to consider this an epidemiologic association rather elastic fibers through an epidermal channel as de- than a discrete entity of perforating dermatoses. scribed earlier. Main58described a quick diagnostic Disseminated EPS. Disseminated EPS has been procedure whereby lesions of EPS are scraped su- reported in six patients with Down‘s ~yndrome,~~,~”perficially with a scalpel and a smear made on a slide one individual with bilateral palmar simian creases that is then stained with Giernsa stain. This Roman- who was otherwise normal,50 and one patient with ofsky stain induces the elastic fibers to appear bright osteogenesis im~erfecta.~~ red with a basophilic periphery. Although this diag- Miscellaneous Conditions. There are numerous nostic test may be specific for EPS and possibly other other defects, both cutaneous and systemic, that are disorders of elimination, further studies to indicate tenuously associated with EPS,39including case reports specificity of this diagnostic technique are required. of Rothrnund-Thompson ~yndrome,~’bone defects, keratosis pilaris, ichthyosis, keratoderma of the palms Treatment and soles, hyperpigmentation, ecchymoses, alopecia, In most cases EPS is largely refractory to treatment congenital cataract, small stature,39 and folliculitis and does not appear to be affected by any associated ulerythematosa reti~ulata.~’In Christianson’s review disorders. It usually resists destructive therapies. Ro- of 30 cases3’ he found that keloids occurred following senbl~rn’~used a liquid nitrogen spray technique biopsy in 8. Catterall’’ later confirmed this. There with a wide-field spray and treated the lesions of EPS have been two interesting cases of EPS involving the for 8 seconds with complete thawing in 20 seconds. ear, one in an 11-year-old boy with the ear as the Two treatments 7 days apart resulted in complete sole site of involvement and the other in a 12-year- resolution of all lesions without scar formation. These old boy with lesions on the ear in conjunction with lesions had been refractory to intralesional and topical other lesions el~ewhere.~~ steroids. Favorable therapies in other reports have included cellophane tape stri~ping,~,”Dichlorotetra- Genetics oi EPS fluoroethane ~ryotherapy,~’and application of solid carbon dioxide.” More therapeutic failures than suc- The association of EPS with certain genodermatoses cesses have been reported, however, and include is striking, and figures have ranged from 260/03 to topical and intralesional steroids,”~” keratolytic~,~’ 37O/0.’~ MacCaulay presented a patient with EPS and vitamin E (300 mg daily).’” In considering treat- lesions that appeared on one arm to be followed by ment modalities for EPS, one must be cognizant of a a strikingly symmetric lesion of EPS on the other arm. high incidence of keloid formation (27%) when these No 5 TRANSEPIDERMAL ELIMINATION . Woo and Ratmutsen 2 73 individuals have biopsy specimens taken." Unfortu- of the left forearm, he was able to produce lesions nately, the incidence of keloids following treatment by scratching the skin with a 25-gauge needle. Neither attempts is unknown. On the whole, most individuals a tongue blade nor a needle prick was effective in must learn to live a peaceful coexistence with their inducing lesions in a similar site. Since then, several lesions until the lesions resolve spontaneously due author~~'.~~-~'have been able to induce lesions in to some unknown stimulus. the presacral area, upper back, and extensors of the wrist, forearm, and fingers using a variety of methods, Reactive Perforating Collagenosis including pinprick, scratch, and superficial abrasion History with a 4-mm punch. Sites where lesions could not Reactive perforating collagenosis was first described be produced in experiments are the upper in an excellent succinct report in 1967 by Meh~egan.'~ scapula," and flexor f~rearm.~'Cold has been re- His patient was a 6-year-old girl with an unusual ported to exacerbate the total number of lesions in epithelial response to superficial trauma. At 9 months four patient^,^^,^^,^" and four patients reported "intol- of age, she experienced numerous discrete papules erance" to One patient,6' however, reported located over the extremities, many in a linear distri- worsening of the eruption in spring. bution, suggesting Koebnerization of the lesions. His- tologic observations led Mehregansq to suggest the Histology name "reactive perforating collagenosis" (RPC). The histopathology of RPC varies with the age of Clinical Characteristics the lesions, and step sections must be performed on Clinically, RPC starts as a 1-mm papule that evolves all specimens to document the presence of TE of over 3-4 weeks to 6 mm in size and occurs often in collagen.59 Sections of early nonumbilicated lesions sites exposed to trauma (Fig. 3). The papules become show perilesional epidermis to be acanthotic. In the umbilicated and contain a central plug of horny center there is a widened dermal papillae containing material that can be removed with a curette only bluish connective tissue confined to the upper dermis. with some difficulty, often leaving a bleeding crater. There is no underlying inflammatory infiltrate, while With time the central umbilication becomes shallower the overlying epidermis is thinned and the stratum and the plug is eliminated. By 2 months, the lesions corneum has a thin layer of parakeratosis. disappear completely, leaving a scar or area of hy- On examination of older umbilicated lesions, a popigmentation. Although each individual lesion has cup-shaped crater containing a plug, which is para- a finite life span, a person may have recurrent lesions keratotic, with degenerated collagen and numerous that erupt over time, persisting for as long as 37 exocytic inflammatory cells is visible. Masson's tri- years.60 chrome and phosphotungstic acid-hematoxylin stains A total of 47 patients with RPC have been described for collagen reveal that the central plug consists of (Table 2). Approximately 560/0 were male patients refractile hyalinized and altered collagen that is elim- and 44% were female patients. Onset (when indi- inated in a transepidermal fashion. Since the direction cated) was prior to 1 year of age in 18%)and during of elimination is perpendicular to the epidermis, the childhood in 58%. Only 10 patients were reported collagen fibers can be easily seen within the plug with an onset during adulthood (older than 18 years and in numerous small perforations within the un- of age), and they appear to constitute a separate derlying epidermis. The epidermis of the lateral wall group. The extremities are involved in 10O0/o of of the crater is slightly acanthotic with hypergranulosis reported cases, predominantly on the extensor as- and hyperkeratosis. The upper dermis shows a mini- pects. Specific sites include the extensors of the hand mal phagocytic and lymphocytic infiltrate with a slight in 58% of patients, the trunk in 40%, and the face increase in and some authors have in 27%. The vast majority (66%) of patients related reported the additional presence of reactive granu- onset of the lesions to trauma, usually insect bites lat ion tissue .61 and scratches, although precipitation from acne le- On examination of resolving lesions of RPC,'" a sions" or even corporal punishment"' have been much smaller, shallower crater containing predomi- reported. Only two patients specifically denied rela- nantly parakeratotic keratin with only small foci of tionship to trauma.62,63 degenerated collagen is visible. At the base of the Lesions of RPC can be induced experimentally and plug, the epidermis is almost regenerated. Here the may be site-dependent (extensor aspect preferred). malpighian cells appear to contain abundant cyto- BovenmeyerM first reported successfully inducing le- plasm with a large amount of glycogen in larger cells; sions in a 4-year-old girl. Using the extensor surface however, the granular layer is absent and the basal 2 74 INTERNATIONAL JOURNAL OF DERMATOLOGY June 1985 Vol. 24 TABLE2. Reactive Perforating Co//agenosis: Reported Cases Age at Case Age at Onset No. Author Sex Presentation (Years) Type of Trauma Parental Affected Sites Unaffected Areas Consanguinity 1 Kanan" M Early chldhd 26 Scratches and Face, hands (dorsal, feet Trunk, palms, soles Posit ive abrasions 2 Kanan" F Early chldhd 28 Scratches and Face, hands, feet (dorsa) Trunk, palms, soles Positive abrasions 3 Kanan6' M Early chldhd 20 Scratches and Hands & feet Trunk, palms, soles Positive abrasions 4 itanan6' M Early chldhd 40 Scratches and Hands & feet Trunk, palms, soles Positive abrasions 5 Kananbs M Early chldhd 32 Scratches and Hands & feet Trunk, palms, soles Positive abrasions 6 Kana# M Early chldhd 32 Scratches and Hands & feet Trunk, palms, soles Positive abrasions 7 Kanan61 F Early chldhd 24 Scratches, abrasions, Hands & legs Trunk, palms, soles Posit ive & mosquito bites 8 Mehregan" F 9 months 6 Superficial scratches Dorsa of hands, forearms Trunk, palms, soles NS elbows, knees 9 I Weiner" F Early infancy 11 Superficial scratches Scalp, hands (dorsa) Trunk, palms, soles NS arms and legs 10 J Weiner" M Early infancy 6 Superficial scratches Scalp, hands (dorsal Trunk, palms, soles NS arms, legs, and face 11 Mehregan' NS Chldhd Adult Superficial scratches Hands (dorsal. arms Palms, soles NS legs, scalp, trunk 12 Mehregan' NS Chldhd Chldhd Superficial scratches Hands (dorsa), arms, legs Palms, soles NS scalp, trunk 13 Mehregan' NS Adult Adult Superficial scratches Hands (dorsa). arms, legs Palms, soles NS scalp, trunk 14 Mehregan' NS Chldhd Chldhd Scratches and Hands (dorsal. arms, legs Trunk, plams, soles NS (siblings) mosquito bites bites 15 Mehregan' NS Chldhd Chldhd Scratches and Hands (dorsa), arms, and Trunk, palms. soles Negative mosquito bites legs 16 Mehregan' NS Chldhd Chldhd Scratches and Hands (dorsa), arms & Palms, soles, NS (siblings) mosquito bites legs bites upper thighs 17 Mehregan' NS Chldhd Chldhd Scratches and Hands (dorsal, arms & Palms, soles NS mosquito bites legs 18 Mehregan' NS Chldhd Adult Scalp, hands (dorsa), Palms, soles NS arms, legs, trunk 19 Mehregan' NS Chldhd Chldhd Scratches and Hands (dorsa), arms, legs Trunk, palms, soles NS (siblings) mosquito bites bites 20 Mehregan' NS Chldhd Chldhd Scratches and Hands (dorsal, arms, legs Trunk, palms, soles NS mosquito bites 21 EovenmyeP F 4 years 6 Cat scratches, insect Face, extensor legs. Palms, soles, Negative bites forearms, buttocks upper thighs 22 A WeineP' M 1 year 6 on one Sites of corporal Face, extremities, trunk Palms. soles NS occasion punishment 23 A WeineP' F 18 mnths 8 Not constantly Face, extremities. trunk Palms, soles NS obtained 24 Mohrib' M 20 20 None Elbows. not linear Rest of body NS 25 Shitara" NS NS Adult NS NS NS NS 26 Miwa" NS NS Adult NS Hands, elbows, buttocks Palms, soles NS 27 NairM M 10 51 NS Extensor extremities with Trunk, palms, soles Negative Koebner 28 Nairw M 3 40 NS Dorsa hands, extensor Mucosal NS (father) extremities face, scalp, palms, soles (all over) 29 NaiP F 3 12 NS Extensor extremities and NS Pmitive (children) trunk 30 NaiP F 5 10 NS NS NS Positive (children) 31 NairbO M NS 1 Y2 NS Extremities NS Positive (children) 32 Fretzinb' F 5 24 Insect bites, acne Arms, legs NS NS papules 33 Iillson" M 1 1 NS Back 01 hands, arms Trunk. palms, soles NS (siblings) elbows, knees No. 5 TRANSEPIDERMAL ELIMINATION . Woo and Rasmussen 2 75 TABLE2. Continued Age at Case Author Sex Age at Onset No. Presentation (Years) Type of Trauma Parental Affected Sites Unaffected Areas Consanguinity 34 jillson" M 1 4 NS Back of hands, arms, Trunk, palms, soles NS elbows, knees 35 Poliak'' F Black adult 41 NS (on dialysis) Extensor extremities Trunk, palms, soles NS 36 Poliak* F Black adult 51 NS Extensor extremities, Palms, soles NS trunk, face 37 Poliakb* M Black adult 80 Scratch (on dialysis) Extensor extremities, Palms, soles NS trunk, face 38 Poliakbb F Hispanic 57 Scratch (on dialysis) Extensor extremities, Palms, soles NS adult trunk, face 39 Poliakbb M Hispanic 77 NS Extensor extremities, Palms, soles NS adult trunk, face 40 PoliakM M Black adult 65 Scratch (on dialysis) Extensor extremities Trunk, palms, soles NS 41 Coc hrar~'~ F Black adult 41 NS (on dialysis) Trunk, arms, central hack Palms. soles NS 42 Co(hr.~n'~ F Black adult 36 NS (on dialysis) Extensor arms, upper Palms, soles NS back 43 Cullrd' F Black 19 Insect bite, scratch Dorsa hands, extensor Palms, soles NS chldhd forearms, trunk, thighs 44 Pdsri(hdbS M 3 23 NS Extensor extremities Trunk, palms, soles NS 45 Bingul" F 3 11 Cat scratch Oorsa hands, extremities. Trunk, palms, soles NS extensors, flexors 46 Nyfors" M 1 month 3 Tree scratches Begin on trunk, then Palms, soles NS [Siblings) face, extremities. dorsa hands 47 Nyfors" M 5 7 NS Extremities, face, dorsa Trunk, palms, soles NS hands NS. not significant. cell layer appears to be incompletely developed with pathogenetic effects can be constructed as follows. a partially organized basement membrane. The re- In response to trauma, injury to dermal connective maining altered dermal collagen is eliminated through tissue occurs, resulting in alteration of papillary col- a narrow tunnel within the epidermis in the center lagen. Reactive epithelial hyperplasia in the adjacent of the lesion, the lining epithelium of the tunnel epidermis occurs, while the directly overlying epi- being well-organized. The underlying dermis shows dermis becomes thin and shows multiple foci of slight vascularity and minimal inflammatory infiltrate. disruption through which altered collagen and sparse Stains for calcium, elastic tissue, and acid muco- inflammatory cells are eliminated. As underlying der- polysaccharide are negative in the plug and exhibit mal material is transferred from the dermis to the no increase in the dermal papillae at any stage. surface, the epidermis sinks into this area, which was Similar light-microscopic features are seen in both formerly occupied. The process of TE continues naturally occurring lesions of RPC and experimentally unabated until the entire supply of altered collagen induced lesions." Electron-microscopic examination of the epidermis in early lesions shows complete disappearance of the basal lamina. Desmosomes are intact, but bundles of normal-appearing collagen fibers appear interspersed within widened intercellular spaces." Mohrib3studied the dermis of a regressing lesion and found that the collagen was disrupted by large masses of fine fila- mentous material, accumulations of small vesicular bodies, and phagocytes. As to the pathogenesis of this disorder, RPC lesions are almost always invoked by some sort of superficial FIG. 3. Linear Koebner phenomenon in lesion of reactive perforating collagenosis (RPC). Individual morphology of RPC trauma, although interestingly deeper wounds, such consists of umbilicated papules in a linear arrangement on the as surgical incisions, do not induce lesions." The dorsa of the extremities. (Courtesy of Scott W. Bronstein, M.D.) 276 INTERNATIONAL JOURNAL OF DERMATOLOGY June 1985 Vol. 24 TABLE3 Cases of RPC with Adult Onset Author Onset Sex Dlabetes Nephropathy Dlalysls Retlnopathy Prur~tus Other Mehregan' Adult - - Yes Yes - ~ Mohrib' 20 yrs - - - - ~ - Wegener's granulomatosis Poliak% Adult F Ye5 Ye5 Ye5 Ye5 Ye5 Adult F Yes Yes No Yes Ye5 Adult M Yes Yes Ye5 Ye5 Yes Adult F Y e5 Ye5 NO Ye5 Yes Adult M Yes - No Yes Ye5 Adult M Yes - Yes Ye5 Yes C~chran'~ 41 yrs F Yes Yes Yes Yes Ye5 RPC cleared with UVB 36 yrs F Yes Ye5 Yes - Y e5 RPC treated with UVB is exhausted. At this point, a repair phenomenon so-called Kyrle's disease on the basis of many criteria occurs in which epidermal reconstitution closes off (discussed below), such as the presence of linear the eliminating channels. The keratotic plug at the Koebnerization, the tendency to remain discrete, and surface gradually sloughs off via normal epidermal the presence of TE of collagen. turnover, leaving minimal or no scarring. Genetics of RPC Association with Other Disorders There were 25 patients (52%) with RPC who had affected family members (mostly siblings). Of these Conditions associated with RPC include: ri~ketts,~' 25 patients, 10 had a history of parental consanguinity. ricketts-like bone change^,'^ bilateral coxa era,^^ Considering this genetic background, the evidence Wegener's granulomat~sus,"~lichen amyloidos~s,~~ leads us to postulate an autosomal recessive mode rheumatoid arthriti~,'~and Henoch-Schonlein pur- of inheritance, although further genetic studies are p~ra.~' necessary to delineate more clearly the mechanism There appears to be a specialized subset of RPC, of transmission. defined by adult onset and the presence of diabetes mellitus. These cases are summarized in Table 3. Ten Treatment cases of RPC with onset in adulthood (older than 18 years of age) were recorded in the Iiterat~re.',"~~''~~~~'~Treatment of this disorder is often frustrating and Of these 10 patients, 8 had diabetes mellitus (7 of unrewarding. Recently Cullenh7 treated a 25-year-old the 8 had diabetic nephropathy), 1 had chronic renal woman with tretinoin O.l(yo cream, which decreased disease and was on dialysis (it was not stated whether the total number from 12-21 to 0-2 lesions. Oral diabetes was present),' and 1 had Wegener's granu- forms of treatment have included: antibiotic^,""^^'^^'^' lomat~sis.~'Of all the patients with diabetes and RPC such as erythromycin and tetracycline; oval vitamin (a total of nine),'0,66,76eight fall into the group defined A 100,000 Units daiIyb7~"; oral prednisone 20-50 above (with onset of RPC in adulthood), while the mg/da~'~;rnethotrexate, with some response""; and sole diabetic with onset at 10 years of age had only oral proteolytic enzyme AnanaseTM, 200 rng tid.'" "mild" diabetes. Thus using the criteria of onset of Other agents have included topical keratolytic~~~~~"; RPC in adult years, the physician must be alert to topical steroids with or without occlusion'"; intrale- the concomitant presence of diabetes mellitus, which, sional steroids7'; and ultraviolet light B in diabetic if present, may be severe with diabetic nephropathy. patients on renal dialysi~.~"lsotretinoin undoubtedly Patients with diabetes and RPC had lesions resembling would be of some benefit, especially since it affects classical RPC in all aspects, except for age of onset keratinization and prior responses to topical tretinoin and a tendency to be pruritic although dialysis- have been encouraging. induced pruritus may be responsible in some cases. Cullen"" was able to treat the pruritus successfully Collagenome Perforant verruciforrne with UVB light. P~liak"~was able to induce skin lesions experimentally in two of his patients with Collagenome perforant verruciforrne (CPV) was diabetic adult onset RPC. Lesions of RPC differ from first described by Woringer and Laugier in 1963."',"' No. 5 TRANSEPIDERMAL ELIMINATION . Woo md Rdsrnutcen 277 A 19-year-old man had numerous cuts and lacerations after falling through a glass roof. Three weeks later, flesh-colored hyperkeratotic papules developed in the sites of lacerations consisting of 2-5 mm erythe- matous papules arranged in linear or grouped config- urations. Remission was evident without treatment within 3 months, with almost complete disappearance of the lesions. Histologic examination showed papil- lomatosis and hyperkeratosis with a channel disrupting the epidermis. Within this space were basophilic nonelastic collagen bundles extruding from the dermis to the surface of the skin. Later, Delacretaz and Cattlen" described another case of CPV in a 6-year- old boy who sustained trauma to his right thigh. Three weeks later, a 2 X 4.5-cm plaque appeared at the site of injury, consisting of 30-40 papules, each FIG. 4. A painful nodule with a central plug is present on the helix of the ear, consistent with chondrodermatitis nodularis helicis with a central keratinous plug. The plaque resolved chronica (CNHC). (Courtesy of Detlef K. Coette, M.D.) within 3 months. They presented two other atypical cases-a 12-year-old boy following injection of a corticosteroid and a 30-year-old woman following epidermis was acanthotic or exhibited pseudoepithe- removal of a mole-calling these examples of TE of liomatous hyperplasia with a central crater-like traumatically altered collagen. depression and channel (Fig. 5). The underlying dermis Although CPV and RPC are similar in many aspects, contained a homogeneous fibrinoid material in a they differ in several ways.82 CPV evolves in a single milieu of altered dermal collagen. The collagen bun- episode, without reported familial background (al- dles were swollen and intensely eosinophilic. Elastic fibers often showed degeneration where dermal though the number of reported cases is extremely changes were most prominent. Granulation tissue, a small). RPC does not always have a history of specific chronic granulomatous and inflammatory infiltrate, immediate trauma, appears mostly on the dorsa of telangiectasias, and solar elastosis could be seen in the fingers, and has onset in childhood or in adult the majority of specimens. There was evidence of diabetics and can continue up to 37 years (although underlying perichondritis. Changes in the cartilage individual lesions resolve in 1-2 months)."" Until the were found by BardRSto inconsistent, whereas number of reported cases of CPV has increased, one be Goettes3found 10 of 17 biopsy specimens contain cannot generalize about the true nature of this entity to "degenerated" cartilage. Abnormal collagen may be and probably best regard it as a separate but very the inciting factor in the pathogenesis. It has been closely related entity to RPC. Chondroderrnatitis Nodularis Helicis Chronica Chondrodermatitis nodularis helicis chronica (CNHC) probably represents a distinct separate entity with TE as the primary pathologic event. In 1980, Goettee3 and Cruzs4 independently proposed that the pathogenesis of CNHC was due to this form of elimination. CNHC almost exclusively affects Cauca- sian males in their middle years. Typical appearance is a well-defined %-cm nodule that appears pink to pearly-grey. The lesions appear most often on the helix and rarely on the anthelix (Fig. 4). There is an adherent central crust that, on removal, will reveal a small erosion or cup-shaped depression with a pin- point channel. These lesions may be bilateral and FIG. 5 Histopathology of CNHC demonstrating transepidermal can be quite tender, especially with pressure. elimination TE of altered dermal collagen (X100) (Courtesy of Bardss reviewed 24 cases in which the adiacent Oetlef K. Coette, M D ) 2 78 INTERNATIONAL IOURNAL OF DERMATOLOGY June 1985 Vol. 24 proposed that is primary disorder of 20. Abel M. Elastosis perforans serpiginosa associated with peni- CNHC a TE, cillamine. Arch Dermatol. 1977;113:1303. representing a perforating actinic granuloma.*' Anat- 21. Hashimoto K, McEvoy 6, Belcher R. Ultrastructure of penicil- omy, vascular deticiency, trauma, and actinic damage lamine-induced skin lesions. 1 Am Acad Dermatol. 1981;4: 300-315. may also be important in the pathogenesis. 22. Reymond IL, Stoebner P, Zambelli P, et al. 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A case of reactive perforating elastosis: a feature of certain genetic disorders. Johns Hop- collagenosis observed in a patient with rheumatoid arthritis. kins Med ]. 1962;111:235-251. Clin Dermatol. 1978;32:439-444. 55. MacCauley WL. Symmetry in elastosis performs serpiginosa: 75. Bronstein S. Reactive perforating collagenosis in a patient with its significance. Arch Dermatol. 1963;88:215-217. Henoch-Schonlein purpura. Presented at American Acad- 56. Woerdman MI, Bour DJH, Bijlsma JB. Elastosis performs emy of Dermatology Meeting, New Orleans, December serpiginosa: report of a family with chromosomal investi- 1983. gation. Arch Dermatol. 1965;92:559-560. 76. Cochran RJ, Rucker SB, Wilkin JK. Reactive perforating colla- 57. Ayah F, Donofrio P. Elastosis performs serpiginosa: report of genosis of diabetes and renal failure. Cutis. 1983;31:55-. a family. Dermatologica. 1983;166:32-37. 58. 58. Main RA, Dave VK, Carr A]. Elastosis performs serpiginosa: a 77. Cochran RJ, Tucker SB, Wilkin JK. Reartive perforaling (olla- diagnostic measure. Br J Dermatol. 1971;85:195-196. genosis and diabetes melitis and renal failure. Cutis. 1983;31- 59. Mehregan AH, Schwartz OD, Livingood CS. Reactive perforating 55-58. collagenosis. Arch Dermatol. 1967;96:277-282. 78. Mehregan AH. Perforating dermatoses: a rlinicopathologir 60. Nair BKH, Sarojini PA, Basheer AM, et al. Reactive perforating review. Int J Dermatol. 1977;16:19-27. collagenosis. Br J Dermatol. 1974;91:399-403. 79. Weiner I. Kyrle’s disease: hyperkeratosis follicularis et para- 61. Fretzin DF. Reactive perforating collageneosis. Arch Dermatol follicularis in cutem penetrans in siblings. Arch Uermatol 1974;109:750. 1967;95:329-330. 62. Weiner AL. Reactive perforating collagenosis. Arch Dermatol. 80. Woringer F, Laugier P. Collagenoma perforans verruciforme. 1970;102:540-544. Derm Wochenschr. 1963;147:64-68. 63. Mohri S, Sano T, Fukuda. An adult case of reactivr perforating 81. Laugier P, Woringer F. Keflexions au su1t.t d’un collCigt~nonw collagenosis. J Dermatol (Tokyo). 1980;7:363-369. perforant verruciforme. Ann Dermatol Syphilol. 196 3;90: 29-36. 64. Bovenmyer DA. Reactive perforating collagenosis, experimental 82. Delacretar, Cattlen JM. Transepidermal t4imination of trau- production of the lesion Arch Dermatol. 1970;102:313- malically altered collagen. Drrmatologita. 197h;l52:65 71 317. 83. Coette DK. Chondrodermatitis nodularis rhronira ht4c 15: Phototherapy Phototherapy has lately resumed a respectability lacking since the turn of the century and tht. days of Finsen In medicine, phototherapy and photo